Anticoronaviral Activity of the Natural Phloroglucinols, Dryocrassin ABBA and Filixic Acid ABA from the Rhizome of Dryopteris crassirhizoma by Targeting the Main Protease of SARS-CoV-2

Abstract

The rhizome of Dryopteris crassirhizoma Nakai. (Dryopteridaceae) has been used in traditional medicine in East Asia and has recently been reported to have anticancer, anti-inflammation, and antibacterial activity as well as antiviral activity. Natural phloroglucinols from D. crassirhizoma, dryocrassin ABBA and filixic acid ABA were reported to inhibit influenza virus infection with an inhibitory activity on neuraminidase. In this study, we found that dryocrassin ABBA and filixic acid ABA have an inhibitory activity against the main protease of SARS-CoV-2. Therefore, dryocrassin ABBA and filixic acid ABA exhibited inhibitory activity against SARS-CoV-2 infection in Vero cells dose-dependently using the immunofluorescence-based antiviral assays. Moreover, these compounds inhibited SARS-CoV and MERS-CoV infection, suggesting their broad-spectrum anticoronaviral activity. In addition, a 5-day repeated-dose toxicity study of dryocrassin ABBA and filixic acid ABA suggested that an approximately lethal dose of these compounds in mice was >10 mg/kg. Pharmacokinetic studies of dryocrassin ABBA showed good microsomal stability, low hERG inhibition, and low CYP450 inhibition. In vivo pharmacokinetic properties of dryocrassin ABBA showed a long half-life (5.5–12.6 h) and high plasma exposure (AUC 19.3–65 μg·h/mL). Therefore, dryocrassin ABBA has therapeutic potential against emerging coronavirus infections, including COVID-19.

Antiviral and antibacterial properties of phloroglucinols: a review on naturally occurring and (semi)synthetic derivatives with potential therapeutic interest

“…In another study, although (1) did not have any significant activity against SARS-CoV 3CL pro , isolated phlorotannins competitively inhibited SARS-CoV 3CL pro in a cell-free/based system with IC50 values ranging from 2.7 to 164.7 μM (61). Other phlorotannins characteristic for brown seaweed [( 5), eckol hexaacetate (65), fucofuroeckol B (66), and bifuhalol hexaacetate (67) (Figure 9)] have been recently reported to exert antagonist effects on selected SARS-CoV targets in silico, namely 3CL pro , RdRp, and S pro . Moreover, the same compounds were analyzed to be druggable with no major violations from all the ADMET profiling parameters (62).…”

Potential herb–drug interactions between anti-COVID-19 drugs and traditional Chinese medicine

“…Pharmacokinetic studies of dryocrassin ABBA showed good microsomal stability and low CYP450 inhibition. In vivo pharmacokinetic properties of dryocrassin ABBA showed a long half-life and high plasma exposure 420 .…”

“…LHQW could effectively regulate drug-metabolizing enzymes and transporters 420 , 421 , 422 , 423 ( Table 6 ). The pharmacodynamic and pharmacokinetic characteristics of each herb of LHQW are summarized below.…”

“…Dryopteridis Crassirhizomatis Rhizoma (Mianmaguanzhong in Chinese) is derived from the dried rhizome and petiole residues of Dryopteris crassirhizoma Nakai 428 . Dryopteridis Crassirhizomatis Rhizoma has an inhibitory activity against the Mpro of SARS-CoV-2 and also represses cytokine storm upon COVID-19 420 , 429 . Previous studies have shown that the major components of Dryopteridis Crassirhizomatis Rhizoma include phloroglucinol, flavonoids, terpenoids, steroids, phenylpropanoids, and aliphatic compounds 430 .…”

Optimization of Ultrasonic-Assisted Extraction of α-Glucosidase Inhibitors from Dryopteris crassirhizoma Using Artificial Neural Network and Response Surface Methodology

“…Trimeric phloroglucinol filixic acid ABA has been identified as responsible for the antiviral effect against influenza A virus H1N1 [8]. Additionally, both filixic acid ABA and dryocrassin ABBA were shown to have dose-dependent inhibitory activity against SARS-CoV-2 infection in Vero cells using immunofluorescence-based antiviral assays [9]. Especially, flavaspidic acid AP and nortrisflavaspidic acid ABB are two phloroglucinols that have been previously identified in D. crassirhizoma and characterized.…”